Intravenous baclofen formulations and treatment methods

ABSTRACT

An intravenous baclofen solution is disclosed, along with methods of dosing and treatment therewith.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 14/997,135, filed 15 Jan. 2016 (the '135 application), which claims the benefit of U.S. provisional application No. 62/103,902, filed 15 Jan. 2015 (the '902 application). The '135 application and the '902 application are both hereby incorporated by reference in their entirety as though fully set forth herein.

BACKGROUND OF THE INVENTION

Baclofen is a muscle relaxant and anti-spastic agent. Spasticity is a common symptom of upper motor neuron injury in individuals with cerebral palsy, multiple sclerosis, acquired spinal cord injury, brain injury, and neurodegenerative disorders. Baclofen is a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and acts as a GABA_(B) agonist at the level of the spinal cord. Baclofen is the generic name for 4-amino-3-(4-chlorophenyl) butanoic acid. It is a white or off-white, mostly odorless crystalline powder with a molecular weight of 213.66, and it is slightly soluble in water. Baclofen's structural formula is

Baclofen is sold under the tradename LIORESAL® in oral (10 mg or 20 mg tablets) and intrathecal (0.05 mg/mL, 0.5 mg/mL, or 2.0 mg/mL) formulations. The intrathecal formulation is used in conjunction with an implanted programmable pump to provide a constant infusion of the drug. There are several circumstances in which patients treated with oral or intrathecal baclofen must abruptly discontinue therapy. For example, the programmable pump and/or catheter used in intrathecal administration may need to be removed, refilled, or replaced. Moreover, patients taking oral baclofen may be unable to do so during periods of illness, noncompliance, or surgery, for example. Abrupt discontinuation of oral or intrathecal baclofen can result in a severe withdrawal syndrome characterized by rebound increases in muscle tone and spasms, status epilepticus, hallucinations, and a neuromalignant syndrome-like picture potentially resulting in rhabdomyolysis and multisystem organ failure. The current recommended management of baclofen withdrawal is inadequate, and symptoms are often difficult to control. Agarwal et al., A Pilot Study Assessing Pharmacokinetics and Tolerability of Oral and Intravenous Baclofen in Healthy Adult Volunteers, J Child Neurol., (Jul. 14, 2014), http://jcn.sagepub.com/content/early/2014/07/11/0883073814535504.

Thus, there is a clinical need for an intravenous baclofen formulation to prevent or minimize complications resulting from interrupted oral or intrathecal therapy.

BRIEF SUMMARY OF THE INVENTION

An intravenous baclofen solution is disclosed, along with methods of dosing and treatment therewith. It is believed that intravenous administration of baclofen can permit rapid attainment of necessary drug concentrations, as well as accurate and precise dose titration, thereby allowing for more efficient and effective treatment of withdrawal symptoms or preventing withdrawal altogether.

One embodiment of the invention provides a method of temporarily treating a subject with baclofen during a period of medical fluctuation that comprises (a) discontinuing oral or intrathecal administration of baclofen to the subject; (b) administering to the subject a bolus intravenous dose of a therapeutically effective amount of a solution comprising baclofen at a concentration of up to about 2.0 mg/mL over a time period of about 5 minutes to about 60 minutes; (c) repeating administration of the bolus intravenous dose of baclofen about every 6 to 8 hours until oral or intrathecal administration of baclofen can be resumed; (d) discontinuing administration of bolus intravenous doses of baclofen; and (e) resuming oral or intrathecal administration of baclofen.

In another embodiment, a method of intravenously administering baclofen to a subject that has previously been treated with oral baclofen in a therapeutically effective amount comprises (a) discontinuing oral administration of baclofen to the subject; (b) administering to the subject a bolus intravenous dose of solution comprising about 75% of said amount of baclofen over a time period of about 5 minutes to about 60 minutes; (c) repeating administration of the bolus intravenous dose of baclofen about every 6 to 8 hours until oral administration of baclofen is resumed; (d) discontinuing administration of intravenous baclofen; and (e) resuming oral administration of baclofen.

In another embodiment, a method of temporarily treating a subject with baclofen during a period of medical fluctuation comprises (a) discontinuing oral or intrathecal administration of baclofen to the subject; (b) starting a continuous intravenous infusion of a therapeutically effective amount of a solution comprising baclofen at a concentration up to about 2.0 mg/mL over a time period of about 24 hours; (c) continuing the infusion about every 24 hours until oral or intrathecal administration of baclofen is resumed; (d) discontinuing the continuous intravenous infusion; and (e) resuming oral or intrathecal administration of baclofen.

In another embodiment, a method of intravenously administering baclofen to a subject that has previously been treated with oral baclofen in a therapeutically effective amount comprises (a) discontinuing oral administration of baclofen to the subject; (b) administering a continuous intravenous infusion of solution comprising about 75% of said amount of baclofen over a time period of about 24 hours; (c) continuing the infusion about every 24 hours until oral administration of baclofen is resumed; (d) discontinuing administration of the continuous intravenous infusion; and (e) resuming oral administration of baclofen.

In another embodiment, a method of converting an oral dose of baclofen to an intravenous dose of baclofen comprises (a) determining the oral dose; and (b) multiplying the oral dose by between about 0.45 and about 1.0 to determine the intravenous dose.

In another embodiment, a pharmaceutical solution comprises an effective therapeutic amount of up to about 2.0 mg/mL baclofen dissolved in at least one of normal saline, dextrose solution, Lactated Ringer's solution, or any combination thereof; wherein the solution is adapted to be intravenously administered to a subject.

DETAILED DESCRIPTION OF THE INVENTION

Each milliliter of intravenous baclofen solution can contain about 0.5 mg to about 2.0 mg of baclofen and an isotonic amount of sodium chloride dissolved in sterile water. In an embodiment, the concentration of baclofen in the intravenous solution can be about 0.5-2.0 mg/mL. In an embodiment, the intravenous baclofen solution can include a dextrose solution or Lactated Ringer's solution instead of or in combination with normal saline. The intravenous baclofen solution can further include an anticonvulsant drug, an antispasmodic drug, an anticholinergic drug, and/or an antibiotic.

The present invention also provides a correlation between oral and intravenous dosing of baclofen (see, e.g., Example 2 below). In particular, an equivalent dose of intravenous baclofen can be determined by multiplying the oral dose of baclofen by about 0.45 to about 1.0, preferably by about 0.6 to about 0.9, and more preferably by about 0.75.

Generally, an effective amount of the above-described intravenous baclofen solution can be administered intravenously to temporarily treat a patient during a period of medical fluctuation resulting in the discontinuation of oral or intrathecal baclofen. Temporary treatment with intravenous baclofen may be necessary as bridging therapy (e.g., when a patient is temporarily unable to take oral or intrathecal baclofen) or for management of withdrawal symptoms, for example. As used herein, a “period of medical fluctuation” refers broadly to a time period during which a patient experiences an illness, condition, change in health status, or situation requiring an adjustment to his/her normal medical care or treatment plan. More specifically, a period of medical fluctuation can include at least one of a scheduled or unscheduled surgical procedure, trauma, ileus, bowel obstruction, vomiting, diarrhea, gastrointestinal malabsorption, seizure, stroke, subarachnoid hemorrhage, or patient noncompliance. Furthermore, for patients with implanted intrathecal pumps, periods of medical instability can include an intrathecal hardware failure or a necessity to remove, refill, or replace the intrathecal hardware.

In one embodiment of the invention, a method is provided to temporarily treat a patient with intravenous baclofen during a period of medical fluctuation that comprises discontinuation of oral or intrathecal administration of baclofen to the patient, followed by administration of an intravenous bolus dose of a therapeutically effective amount of a baclofen solution (e.g., between about 1 mg and about 50 mg baclofen per bolus dose) over a time period of about 5 to 60 minutes. The intravenous bolus dose can be administered repeatedly about every 6 to 8 hours until oral or intrathecal administration of baclofen can be resumed. Once intravenous bolus doing has been discontinued, oral or intrathecal administration of baclofen can be resumed.

In another embodiment of the invention, a method of temporarily treating a patient with intravenous baclofen during a period of medical fluctuation is provided that can include discontinuation of oral or intrathecal administration of baclofen, followed by administration of a continuous intravenous infusion of a therapeutically effective amount of a baclofen solution continued until oral or intrathecal administration of baclofen can be resumed. Once continuous intravenous infusions have been discontinued, oral or intrathecal administration of baclofen can be resumed. It is believed that continuous intravenous infusion of baclofen can mimic intrathecal administration of baclofen, can eliminate or mitigate any peaks or troughs in baclofen levels in a patient's cerebral spinal fluid or blood (which may occur during intravenous bolus administration, for example), and can reduce the risk or incidence of adverse events associated with intravenous baclofen.

The invention will be further described by the following detailed examples.

Example 1—Preparation of Intravenous Baclofen Solution

108 g of sodium chloride were placed in a 600 ml beaker and then added to a 20 L beaker containing 8.4 L of sterile water for injection. The resulting sodium chloride solution was stirred in the 20 L beaker until dissolution occurred. Approximately 50 ml of sterile water for injection were used to rinse any residual sodium chloride from the 600 ml beaker, and the rinsings were added to the 20 L beaker. Next, 24.1 g of baclofen powder were placed in a 1 L beaker and then gradually (over a time period of about 2 hours) added and dissolved in the solution in the 20 L beaker. Approximately 50 ml of sterile water for injection was used to rinse any residual baclofen from the 1 L beaker, and the rinsings were added to the 20 L beaker. Approximately 3500 mL of sterile water for injection were then added to the 20 L beaker, and the solution was mixed for a minimum of 10 minutes to ensure homogeneity. The solution was then filtered using a Mini Kleenpak™ (0.2 μm) filter at 20 rpm.

An automated, aseptic filling machine was used to fill approximately 1090 13.5-mL glass vials with approximately 11.0 ml of the solution per vial. The vials were then stoppered, caps were placed on the vials, and the caps were crimped. The vials were stored at about 15 degrees Celsius to about 25 degrees Celsius.

Example 2—Administration of Intravenous Baclofen

A. Subjects

Twelve healthy human volunteers were recruited. The volunteers were medication free for 48 hours before, during, and 24 hours after the administration of the study drug.

B. Study Design

The 12 volunteers participated in a randomized, open-label, 2-way crossover study to compare the pharmacokinetics and bioavailability of oral baclofen with an intravenous baclofen formulation. The oral formulation was a 10 mg baclofen tablet. A single intravenous dose of 5 mg was administered over 15 minutes, using the commercially available 2 mg/mL intrathecal baclofen formulation (Lioresal Intrathecal). Blood samples (6 mL) for the measurement of plasma concentrations of baclofen were collected in blood collection tubes containing K2 ethylenediaminetetraacetic acid at the following times: prior to dosing; at 5, 15, and 30 minutes; and at 1, 2, 4, 6, 8, 10, 12, and 24 hours after drug administration.

C. Determination of Baclofen Concentration in Plasma

Study plasma samples were prepared by adding 50 μL of a 500 μg/mL levetiracetam solution (internal standard) to 250 μL of K2 ethylenediaminetetraacetic acid (EDTA) human plasma. Baclofen and the internal standard were extracted from plasma by precipitating the protein with methanol and drying it under nitrogen at approximately 40° C. The dried residues were reconstituted in 300 μL of a mobile phase consisting of 20 mM ammonium acetate-methanol (75:25) solution. After 1 minute of vortex mixing, the reconstituted sample solution was filtered and injected onto the high-performance liquid chromatograph-mass spectrometer system. Standard curve samples over a range of 20 to 400 ng/mL baclofen and quality control samples containing 30 (low), 80 (medium), and 240 ng/mL (high) baclofen were prepared and analyzed in triplicate along with the study samples. The assay was linear over the range 20-400 ng/mL with a lower limit of quantification of 20 ng/mL.

Baclofen concentration-time data were analyzed using a noncompartmental pharmacokinetic approach with Phoenix software (version 6.2; Pharsight Corporation, Mountain View, Calif.). The terminal rate constant (λz) was determined from the slope of the terminal log-linear portion of the plasma concentration-time curve, and the terminal half-life (t_(1/2)) was calculated as ln 2/(λz). Maximum plasma concentrations (C_(max)) and time to maximum concentration (T_(max)) were determined by direct observation of the data. The area under the concentration-time curve to the last nonzero plasma concentration (C_(last)) that was above half the lower limit of quantification (10 ng/mL) was calculated by the trapezoidal rule and reported as AUC_(last). The area under the concentration-time curve extrapolated to infinity (AUC_(0-∞)) was calculated as AUC_(last)+(C_(last)/λz). Mean and standard deviation values for the parameters were also obtained using the descriptive statistics tool in Phoenix version 6.2. A paired t-test was used to determine if statistical differences existed in log normalized, dose-adjusted area under the curve between oral and intravenous arms.

D. Results

A summary of the pharmacokinetic parameters is presented in Table 1. The mean concentration-time profiles for both (5 mg intravenous and 10 mg oral) arms are shown in FIG. 1. When the subjects received the intravenous formulation, the observed maximum baclofen concentration occurred at the 5-minute time point, whereas the median Tmax for oral administration was 1 hour. The mean (standard deviation) Cmax values for the oral (10 mg) and intravenous (5 mg) doses were 176 (15) ng/mL and 313 (75) ng/mL, respectively (FIG. 1). The mean t_(1/2) was similar for both the oral and intravenous arms (4 and 4.52 hours, respectively). The mean absolute bioavailability of the oral baclofen tablets (Table 1) was 74%. There was a significant difference in log-normalized, dose-adjusted area under the curves (P=0.0024) between oral and intravenous dosing with similar variability (coefficient of variation: 18%-24%).

TABLE I Mean ± SD of Baclofen Pharmacokinetic Parameters Following Oral (10 mg) and Intravenous (5 mg) Administration. 5 mg IV 10 mg oral Pharmacokinetic parameter (mean^(a) ± SD) (mean ± SD) C_(max) (ng/mL) 310 ± 74 174 ± 16  T_(max) (h)^(b) — 1.0 (0.5-2.0) AUC_(last) (ng · h/mL)  593 ± 111 878 ± 199 AUC₀₋

 (ng · h/mL)  707 ± 166 1023 ± 232  AUC₀₋

/Dose^(c) 141 ± 33 102 ± 23  (ng · h/mL/mg) Bioavailability (%) — 74 ± 15 T_(1/2) (h) 4.52 ± 1.6 4.03 ± 0.73 Abbreviations: AUC, area under the curve; IV, intravenous; SD, standard deviation. ^(a)Mean values are presented as arithmetic means ^(b)Median (min, max) reported for T_(max). ^(c)Two-tailed P value < .05 (paired t-test performed on dose-normalized area under the curve)

indicates data missing or illegible when filed

The investigational intravenous formulation was well tolerated. All treatment-emergent adverse events were characterized by the investigator as being mild in severity, and all subjects returned to their baseline values within 6 hours of drug administration.

E. Discussion

This example illustrates that absolute oral baclofen bioavailability is about 75%, indicating that approximately 25% of a 10-mg dose is either not absorbed or undergoes first-pass metabolism prior to drug reaching systemic circulation. This suggests that a smaller intravenous baclofen dose can be used when it is substituted for an oral dose. For example, assuming linear kinetics, the total systemic exposure (area under the curve) after an intravenous dose of 15 mg would be equivalent to the total exposure achieved after 20 mg of oral baclofen dose. Thus, this example suggest that when intravenous baclofen is substituted for oral baclofen, an equivalent intravenous dose will be about 75% of the oral dose.

In one embodiment of the invention, a method of converting an oral dose of baclofen to an intravenous dose of baclofen comprises (a) determining the oral dose; and (b) multiplying the oral dose by between about 0.45 and about 1.0 to determine the intravenous dose. In another embodiment of the invention, a method of converting an oral dose of baclofen to an intravenous dose of baclofen comprises (a) determining the oral dose; and (b) multiplying the oral dose by between about 0.6 and about 0.9 to determine the intravenous dose. In yet another embodiment of the invention, a method of converting an oral dose of baclofen to an intravenous dose of baclofen comprises (a) determining the oral dose; and (b) multiplying the oral dose by about 0.75 to determine the intravenous dose.

All publications, patents, and patent applications cited above are incorporated by reference herein as though fully set forth.

It will be apparent to those skilled in the art that many modifications and equivalents thereof may be made without departing from the spirit and scope of the invention. 

1.-26. (canceled)
 27. A method of determining a therapeutically effective dose of intravenous baclofen for administration to a human subject, the method comprising: determining a therapeutically effective dose of oral baclofen; multiplying the therapeutically effective dose of oral baclofen by between about 0.7 and about 0.8 to determine the therapeutically effective dose of intravenous baclofen.
 28. The method of claim 27, wherein multiplying the therapeutically effective dose of oral baclofen comprises multiplying the therapeutically effective dose of oral baclofen by about 0.74.
 29. The method of claim 27, wherein multiplying the therapeutically effective dose of oral baclofen comprises multiplying the therapeutically effective dose of oral baclofen by about 0.75.
 30. A method of formulating a pharmaceutical solution comprising: determining a therapeutically effective dose of oral baclofen; multiplying the therapeutically effective dose of oral baclofen by between about 0.7 and about 0.8 to determine a therapeutically effective dose of intravenous baclofen; dissolving the therapeutically effective dose of intravenous baclofen in at least one of normal saline, dextrose solution, Lactated Ringer's solution, or any combination thereof.
 31. The method of claim 30, wherein multiplying the therapeutically effective dose of oral baclofen comprises multiplying the therapeutically effective dose of oral baclofen by about 0.74.
 32. The method of claim 30, wherein multiplying the therapeutically effective dose of oral baclofen comprises multiplying the therapeutically effective dose of oral baclofen by about 0.75.
 33. The method of claim 30, wherein the dissolving step further comprises formulating the pharmaceutical solution with a baclofen concentration of up to about 2.0 mg/mL.
 34. The method of claim 33, wherein the baclofen concentration is about 0.5-2.0 mg/mL.
 35. The method of claim 33, wherein the baclofen concentration is about 0.5-1.0 mg/mL.
 36. The method of claim 30, further comprising dissolving a therapeutically effective dose of at least one of an anticonvulsant drug, an antispasmodic drug, an anticholinergic drug, or an antibiotic drug in the pharmaceutical solution.
 37. A pharmaceutical solution formed by the method of claim
 30. 38. The pharmaceutical solution of claim 37, comprising baclofen at a concentration of up to about 2.0 mg/mL.
 39. The pharmaceutical solution of claim 38, comprising baclofen at a concentration of about 0.5-2.0 mg/mL.
 40. The pharmaceutical solution of claim 38, comprising baclofen at a concentration of about 0.5-1.0 mg/mL.
 41. The pharmaceutical solution of claim 37, further comprising at least one of an anticonvulsant drug, an antispasmodic drug, an anticholinergic drug, or an antibiotic drug. 